The overall aims are to study the pharmacodynamic aspects of methadone in a large number of methadone maintenance patients under field conditions. This will be done by observing the relationships between 1) the methadone dosage and the corresponding plasma level, 2) the methadone plasma level, and the clinical effects, and 3) by evaluating the factors that determine or influence these relationships. The range of expected plasma levels with a given dose will be defined and patients with extremely low or high level relative to the dose will be studied further. The role of absorption, biotransformation and excretion as factors determining individual variations in the dose- plasma level relationship will be evaluated. Drug-drug interactions will be looked for and the indicated drugs evaluated in in vitro studies using hepatic microsomal enzyme preparations. The relationship between plasma levels and continuing side effects (sedation, constipation) which some patients may have, will be observed. The solvent extraction and gas-liquid chromatographic technique, recently developed by one of the applicants, will be used for the measurement of methadone in human plasma and for the determination of methadone and its metabolites in tissues and biofluids. These data are expected to provide explanation for the varation(s) in the individual responses, help to select the optimal dosage regimen and contribute to the successful management of the patient.